PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a devastating neurodegenerative disorder without an effective disease-modifying treatment. The critical role of myeloid cell in the progression of AD is supported by genome-wide association studies (GWAS) that show strong enrichment of myeloid cell gene variants in the genetic architecture of AD. However, the specific contributions of the immunogenetic variations to the AD pathogenesis and progression remain unknown. This is a particularly critical knowledge gap in preclinical AD, when an effective intervention could still prevent widespread irreversible neurodegeneration. To achieve our long-term goal of to identify therapeutic targets in preclinical AD by better understanding how immunogenetic AD risk variants affect pathophysiology, the objective of this K23 project is to identify, in preclinical AD, specific AD-relevant phenotypes that result from immunogenetic AD risk. Our central hypothesis is that higher immunogenetic AD risk predicts higher AD pathology burden, alters myeloid cell gene expression, and causes faster neurodegeneration and cognitive decline in preclinical AD. We will utilize use a specifically targeted polygenic risk score to capture the aggregate immunogenetic AD risk, and investigate our hypothesis in large samples of >4,000 clinically normal (CN) older adults from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) screening dataset and 270 CN older adults from the Harvard Aging Brain Study (HABS). We will test our hypotheses by determining the contribution of immunogentic AD risk to (1) cross-sectional AD pathology (as estimated by amyloid/tau PET) (A4/LEARN/HABS), (2) altered expression of myeloid cell gene co-expression modules (HABS), and (3) longitudinal progression of tau pathology, neurodegeneration, and cognitive decline (HABS). During his K23 Patient-Oriented Research Career Development Award period, the candidate's short-term career goal is to transition to an independent clinical investigator elucidating the clinical implications of the genetic architecture of AD, with focus on immunogenetic contribution to the progression of preclinical AD. To achieve this goal, the candidate plans to (1) gain expertise in the neuroimaging biomarkers of preclinical AD, (2) enhance genomic/transcriptomic (?omics?) data production and analysis skills, and (3) continue his training in biostatistics. By successfully executing the proposed project and training, the candidate will be in an ideal position to emerge as an independent NIH-funded clinical investigator, and achieve the long-term career goal of leading a collaborative research program to translate advances in omics into personalized prognostication and therapeutic target identification in AD. The candidate is fortunate to be in an ideal environment for his research project and training, with access to exceptional resources and research community at Brigham and Women's Hospital (BWH), Massachusetts General Hospital (MGH), Martinos Center for Biomedical Imaging at MGH, and the Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard.